Drug-resistant tuberculosis (TB) is a major global epidemic and poses a particular threat
to HIV-infected individuals. With limited effective drugs available for treatment,
multidrug-, and extensively drug-resistant TB carry a high mortality rate and threaten
global TB and HIV control efforts.
New and repurposed medications have recently been found to improve survival and cure
rates. Linezolid-a drug initially developed for the treatment of Gram-positive
infections-has considerable anti-TB activity and has been at the center of this treatment
revolution. Since 2018, WHO has recommended that all multi DR/rifampicin-resistant (MDR)
and extensively drug-resistant tuberculosis (XDR) tuberculosis treatment regimens include
linezolid. When given long-term, however, linezolid-associated toxicity-particularly
myelosuppression and peripheral neuropathy-is very common, affecting 50-80% of patients
and often requiring a temporary or permanent discontinuation of therapy. Such
interruptions put patients at risk of treatment failure and the emergence of additional
resistance to linezolid or one of the other drugs in the regimen. As linezolid use
continues to increase worldwide, such resistance could become widespread, squandering a
valuable medication. Previously conducted research has shown that linezolid toxicities
are associated with trough plasma concentration and that the drug has considerable
inter-individual variability. The investigator team, therefore, hypothesize that
therapeutic drug monitoring (TDM) could identify those with higher linezolid
concentrations and permit pre-emptive dose reductions that could avert drug toxicity and
premature discontinuation.
This study will take place at the Nkqubela TB Specialist Hospital in East London, South
Africa. TB diagnosis and initial treatment regimen will be determined by the hospital
clinical team, per local guidelines. Following enrollment, participants will be
randomized after enrollment to either undergo a therapeutic drug monitoring (TDM)
strategy for LZD, or standard of care (SOC). Participants in both arms will have a trough
plasma linezolid concentration drawn approximately one week after enrollment (within one
month of TB treatment initiation). The PK specimens collected from TDM arm participants
will be analyzed by University of Cape Town lab staff. The PK specimens collected from
SOC participants will be stored for future analysis.
Standard treatment for RR-TB in South Africa includes 6 months of therapy, including
linezolid 600 mg daily for duration of treatment. Those in the TDM arm whose
concentration is above a set threshold (2.5 mg/L) will have their LZD dose reduced to
300mg daily, while those in the SOC arm will receive routine monitoring alone. All
participants will be screened monthly for hematologic and neurologic toxicity. Hospital
and clinic providers will manage all treatment other than the TDM-guided linezolid dose
reduction. If participants in either the SOC or TDM arm experience linezolid toxicity,
hospital and clinic providers may choose to temporarily or permanently discontinue
linezolid, regardless of any prior TDM-guided dose reduction, in accordance with South
African national guidelines.
Aim 1 (Primary Outcome Measure of this study) and Aim 2 (the first Secondary Outcome
Measure) are described in the Outcome Measures section. For Aim 3, population PK modeling
will be used to explore the complex relationship between linezolid pharmacokinetic
parameters and the trajectory of toxicities over time. It will also be determined as to
whether those whose dose is lowered still meet exposure targets for drug efficacy. South
Africa has among the highest global burden of drug-resistant TB and HIV and has led the
world in the rollout of new RR-TB drugs and regimens. The aims of this study will answer
fundamental questions about LZD pharmacology that will directly inform its use in South
Africa and worldwide.
